Stroke-like episodes (SLE) occur in phosphomannomutase deficiency (PMM2-CDG), and may complicate the course of channelopathies related to Familial Hemiplegic Migraine (FHM) caused by mutations in CACNA1A (encoding CaV2.1 channel). The underlying pathomechanisms are unknown. We analyze clinical variables to detect risk factors for SLE in a series of 43 PMM2-CDG patients. We explore the hypothesis of abnormal CaV2.1 function due to aberrant N-glycosylation as a potential novel pathomechanism of SLE and ataxia in PMM2-CDG by using whole-cell patch-clamp, N-glycosylation blockade and mutagenesis. Nine SLE were identified. Neuroimages showed no signs of stroke. Comparison of characteristics between SLE positive versus negative patients’ group showed no differences. Acute and chronic phenotypes of patients with PMM2-CDG or CACNA1A channelopathies show similarities. Hypoglycosylation of both CaV2.1 subunits (α1A and α2α) induced gain-of-function effects on channel gating that mirrored those reported for pathogenic CACNA1A mutations linked to FHM and ataxia. Unoccupied N-glycosylation site N283 at α1A contributes to a gain-of-function by lessening CaV2.1 inactivation. Hypoglycosylation of the α2δ subunit also participates in the gain-of-function effect by promoting voltage-dependent opening of the CaV2.1 channel. CaV2.1 hypoglycosylation may cause ataxia and SLEs in PMM2-CDG patients. Aberrant CaV2.1 N-glycosylation as a novel pathomechanism in PMM2-CDG opens new therapeutic possibilities.

Summary:Purpose: To study the risk of recurrence after a first unprovoked seizure in childhood.Methods: All consecutive patients aged less than 14 years with one or more unprovoked seizures who were attended between January 1, 1987, and June 1, 1996, were included in a prospective study. Clinical features of patients attended after a first seizure and those attended after two or more seizures were compared. Recurrence risk in both groups was estimated by Kaplan-Meier curves. Univariate and multivariate analyses of the potential predictors of recurrence risk were performed for the group of patients attended after a first seizure using the Cox proportional hazards model.Results: Included in the study were 217 children. KaplanMeier estimate of recurrence risk was 64% at 5 years, when only patients being attended after a first epileptic seizure were included, compared with 74% when all patients were included. Significant differences in several clinical features were found between patients attended after a first seizure and those attended after two or more seizures. Univariate and multivariate analyses showed that in the overall cohort of patients attended after a first seizure, a symptomatic etiology increased the risk of recurrence, whereas a patient age of 3 to 10 years decreased this risk. In particular, the recurrence risk was 96% at 2 years for symptomatic seizures, compared with 46% for idiopathic/ cryptogenic seizures. In the group of patients with idiopathic/ cryptogenic seizures, an abnormal electroencephalogram and the occurrence of seizures during sleep increased the recurrence risk, whereas a patient aged 3 to 10 years reduced it. In the group of patients with symptomatic etiology, univariate analysis revealed that there was a lower recurrence risk for patients aged 3 to 10 years. This last finding was not maintained, however, in multivariate analysis.Conclusions: The recurrence risk depends on the inclusion criteria for enrolling patients. Several factors enable us to predict the recurrence risk after a first unprovoked seizure; the most important of these factors is the etiology of the seizures.

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